Alcohol use disorders (AUDs) are a major problem in medicine and society, and the few available treatment strategies have so far met with limited success. It is well established that genetic, psychosocial, and environmental factors contribute to an increased risk for AUDs. Our laboratory has pioneered the development of Drosophila as a model system for the identification of genes and molecular pathways that regulate simple ethanol-induced behaviors, such as intoxication and the development of tolerance, and many of the underlying molecular mechanisms have been found to be conserved between flies and mammals. Here, we propose to investigate the mechanisms underlying more complex behaviors - ethanol consumption, preference, relapse, and reward - in Drosophila. The Specific aims of this proposal are: 1) to characterize in detail, using newly developed software, the behavior of flies during ethanol self-administration and relapse, and study the influences of experience as well as social and environmental context; 2) to define the neuromodulators and neural circuits engaged during these behaviors; 3) to establish whether genes that regulate acute ethanol intoxication also mediate ethanol consumption, relapse and reward, and identify novel genes that regulate these behaviors; and 4) to identify potential pharmacotherapies for AUDs by screening a large collection of FDA-approved drugs for their efficacy in curbing ethanol consumption and relapse. The ease, potential for high throughput, and relatively low expense of Drosophila studies make the fly a powerful system to investigate the molecular and neural mechanisms underlying ethanol preference, relapse and reward. These mechanisms will provide novel insights into these complex behaviors, which can be translated to rodent models, provide candidate genes for the genetics of AUDs in humans, and ultimately, suggest potential targets for pharmacotherapy. PUBLIC HEALTH RELEVANCE: We will identify novel mechanisms underlying ethanol self-administration, relapse, and reward in flies, mechanisms which can be then be translated rapidly to preclinical rodent models, provide candidate genes for the human genetics of alcohol use disorders, and suggest new pharmacotherapies for this immense medical and social problem.